The hypothesis that the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG) originates mainly in the central nervous system was tested. Guanethidine, a sympatholytic agent, with minimal ability to penetrate the central nervous system was administered to six hypertensive patients. Excretion of MHPG fell for each patient (range 33-76%); mean reduction for all subjects was 60% (p less than .001). It is concluded that most MHPG is formed in the peripheral sympathetic nervous system.